DESCRIPTION OF PROGRAM PROJECT (provided by applicant): Caliciviruses consist of a family of viruses that infect humans and animals. Human caliciviruses called noroviruses cause gastrointestinal disease, with the disease burden being enormous in all age groups. Death can occur in young children and the elderly. Noroviruses cause almost all outbreaks (>95%) of nonbacterial foodborne and waterborne disease that result in 23 million cases of gastroenteritis annually in the US. Rehydration therapy is currently the only treatment for disease and hand washing may reduce transmission. Diagnosis is challenging because universal primers to detect the viral RNA genome are not available, and no rapid, broadly-reactive enzyme immunoassay is approved in the US. Effective antivirals could be useful to stop spread of virus in semi-closed environments and treat chronically infected individuals. This Program Project application integrates the efforts of a molecular virologist, a physician scientist, a biophysical chemist/microbiologist with expertise in proteomics, a structural biologist, and a newly recruited medicinal chemist interested in small molecule inhibitors. This integrated team will build on previous basic science experience and discoveries to allow rapid progress on current applied needs related to public health and understanding of viral pathogenesis. Project 1 will develop new, broadly-reactive diagnostic assays to detect noroviruses and identify lead antiviral compounds to inhibit key targets required for viral replication. Project 2 will develop methods to propagate noroviruses in cultured cells and dissect the molecular basis of host restriction of viral replication. Project 3 will pursue high resolution structural information on the viral capsid and viral proteins critical for genome replication to facilitate structure -based development and testing of antivirals. Each project is dependent on the experimental and intellectual contributions of 3 Core facilities: the Administration Core, Microscopy Core, and the Protein and Small Molecule Chemistry Core. Proposed, continued research by this Program Project team is expected to make new fundamental discoveries that will be important in the diagnosis, treatment, prevention and understanding of the biology of these epidemiologically significant human pathogens.